1. What every clinician should know

Clinical features and incidence

Acute cystitis occurs in approximately 2-3% of pregnant women. The disorder is characterized by urinary urgency, frequency, dysuria, suprapubic discomfort and, in some patients, a low-grade fever. Gross hematuria may also be evident. Patients with cystitis typically do not have a high fever, chills, flank pain, or costovertebral angle tenderness. These latter findings are more indicative of upper tract infection (pyelonephritis).

Risk factors

Acute cystitis may develop in women who have untreated, or inadequately treated, asymptomatic bacteriuria. More commonly, however, it occurs de novo in women who did not have pre-existing bacterial contamination of the bladder. Risk factors for acute cystitis include recent onset of coitus ("honeymoon cystitis"), use of a diaphragm or spermicides for contraception, prior history of cystitis, diabetes and sickle cell disease. Women who are nonsecretors of ABO blood group antigens are also at increased risk for acute cystitis. In addition, instrumentation of the bladder is another important risk factor for development of acute cystitis. Pregnant women are most likely to be catheterized during labor, when they have an epidural anesthetic, and in anticipation of operative vaginal delivery or cesarean delivery. Of note, multiple intermittent catheterizations pose a greater risk of causing infection than continuous catheterization.

The most common organism that causes acute cystitis, particularly in women who are experiencing their first episode of a urinary tract infection, is Escherichia coli. Other pathogenic aerobic gram-negative bacilli include Proteus species and Klebsiella pneumoniae. Three gram-positive aerobes also play an important role in the pathogenesis of acute cystitis: group B streptococci, enterococci and staphylococci. Unusually virulent gram-negative aerobic bacilli such as Enterobacter, Serratia or Pseudomonas species are uncommon pathogens except in immunosuppressed patients or women who are chronically instrumented (e.g. a patient with bladder dysfunction due to neurological injury.)

2. Diagnosis and differential diagnosis

A. Establishing the diagnosis

If acute cystitis is suspected, the clinician should obtain a urine specimen for analysis and culture. Ideally, the specimen should be obtained by sterile urethral catheterization. If catheterization cannot be performed for some reason or the patient declines the procedure, a midstream sample should be obtained for culture. Surprisingly, the midstream specimen seems to be comparable to a first morning void or a more elaborate midstream clean catch void in preventing contamination from vaginal organisms. One portion of the specimen should be used for point-of-care analysis by dipstick. The key dipstick findings suggestive of bacterial infection are positive tests for nitrites and leukocyte esterase. Clinicians should remember that the nitrite test may be falsely negative if the patient is infected by gram-positive organisms or if the urine has only incubated in the bladder for a very short period of time. In addition, the dipstick methodology is primarily applicable to symptomatic patients. It is not sufficiently sensitive to be used in lieu of culture for detecting bacteriuria in asymptomatic pregnant women.

Attention also should be paid to the urine pH, which normally is in the 5-6 range. An elevation of the pH to 8 is highly suggestive of an infection caused by Proteus species. Identification of this particular organism is of great importance when deciding upon empiric antibiotic therapy, as noted below.

If the presenting episode is the patient's first UTI, the overwhelming probability is that the causative organism is E. coli, and an expensive urine culture can be avoided. However, in any patient with a recurrent infection, urine should be sent to the laboratory for culture and sensitivity analysis because this patient may be more likely to harbor an organism that is resistant to commonly used antibiotics. Treatment should not be delayed while awaiting the result of the culture, but antibiotic therapy may need to be modified, depending upon the result of the sensitivity analysis.

When urine has been obtained from asymptomatic patients by the clean-catch technique, a "positive" culture is usually defined as one showing more than 100,000 colonies/ml of a single uropathogen. However, when urine is obtained from symptomatic patients, particularly by catheterization, the cut-off for defining a "positive" culture is only 100 colonies/ml of a single uropathogen.

When midstream cultures show varying colony counts of "mixed vaginal flora," they may well be contaminated specimens, especially when group B streptococci and enterococci are identified. The presence of E. coli is more likely to be associated with true bladder colonization, as opposed to vaginal colonization. If the clinician determines that a repeat culture is indicated, the specimen should be obtained by catheterization.

B. Differential diagnosis

The disorder most likely to be confused with acute cystitis is acute urethritis (acute urethral syndrome). Patients with acute urethritis typically are not febrile and do not have suprapubic discomfort. However, they may have a purulent urethral discharge, a finding which is not usually present in women with acute cystitis. Although acute urethritis may be caused by low colony counts of aerobic gram-negative bacilli, it is much more commonly caused by gonorrhea, chlamydia or a combination of both organisms.

Patients with a trichomonas vaginal infection also may have dysuria and frequency, but they would not typically have suprapubic discomfort, frank hematuria or a low-grade fever. In these patients, the most prominent physical findings are a greenish-yellow frothy vaginal discharge and multiple punctate hemorrhages on the exocervix ("strawberry cervix").

Another possible explanation for the symptoms of frequency and dysuria would be chemical irritation of the urethral meatus by agents such as bubble bath solutions or douching preparations.

3. Management

At any stage of pregnancy, acute cystitis virtually always can be treated as an outpatient with oral antibiotics. One of the most useful antibiotics for treatment is nitrofurantoin monohydrate macrocrystals (Macrobid). The appropriate dose is 100 mg twice daily.

If Proteus infection is suspected by virtue of a prior positive culture or an elevated urine pH, the patient should be treated with trimethoprim-sulfamethoxazole double-strength (Bactrim or Septra), one tablet twice daily. This drug should not be used in the first trimester of pregnancy or immediately prior to delivery (please see below). Trimethoprim-sulfamethoxazole is less likely than nitrofurantoin to be effective against E. coli and, therefore, should not be used as the first-line agent unless Proteus infection is likely.

Amoxicillin, 875 mg orally twice daily, should be used if enterococcal infection is suspected. Otherwise, amoxicillin is not a good empiric choice for therapy because of a high prevalence of resistance among strains of E. coli and Klebsiella pneumoniae and because of potential side effects, such as drug-induced diarrhea and overgrowth of yeast in the vagina.

The usual duration of treatment should be 3 days for an initial infection and 7-10 days for a recurrent infection. Patients with a history of multiple recurrences may require treatment for a more extended period of time, 2 to 4 weeks. Such patients may harbor organisms in the kidney, and a more protracted course of antibiotics may be necessary to eradicate the focus of infection.

4. Complications

A. Complications from the condition

If lower tract infections are not treated adequately, the obstetric patient may develop an ascending infection (pyelonephritis). Ascending infection results from stasis of urine flow within the ureters caused by the inhibitory effect of progesterone on smooth muscle peristalsis and the compressive effect of the uterus on the ureters, particularly the right ureter. Pyelonephritis, in turn, may be associated with bacteremia, septic shock and ARDS. It also is a major cause of preterm labor.

B. Complications as a consequence of management

The principal complications associated with treatment of acute cystitis are drug-related side effects. Specifically, in rare instances, use of nitrofurantoin in pregnancy has provoked manifestations of G6PD deficiency. Sulfonamides may cause allergic reactions in the adult, including Stevens-Johnson syndrome.

When used in the mother close to term, sulfonamides may displace bilirubin from protein binding sites, resulting in neonatal hyperbilirubinemia. Moreover, recent reports have linked sulfonamide use in the first trimester with birth defects in the baby. Reported abnormalities include neural tube defects, cardiac anomalies, choanal atresia and diaphragmatic hernia.

The major adverse effects of amoxicillin/ampicillin/amoxicillin-clavulanic acid include allergic reaction, diarrhea and vaginal yeast infection. The quinolone antibiotics have been associated with injury to the developing cartilage of the fetus, but the risk of this complication is very low.

5. Prognosis and outcome

A. Maternal and fetal/neonatal outcomes

A single episode of acute cystitis that is properly treated should not cause any adverse pregnancy outcome. However, it is essential to make certain that the infection has been eradicated. Therefore, a follow-up culture for "test of cure" should be performed 1-2 weeks after the patient finishes her prescribed course of treatment. Persistent UTIs, particularly those that evolve into upper tract infections, may cause complications. Approximately 25% of patients with a single episode of cystitis will develop a recurrent infection within one year. 3-5% will have subsequent recurrences.

B. Long-term maternal health

Isolated episodes of uncomplicated lower urinary tract infections such as asymptomatic bacteriuria and acute cystitis do not lead to renal disease and do not adversely affect the patient's long-term health. Chronic, recurrent infections are often associated with silent upper tract infection and can result in renal injury. Therefore, patients who have a troubling history of recurrent lower UTIs should be counseled about the following preventive measures:

They should wipe from the front to the back after defecating.

They should void shortly after each episode of coitus.

They should not use the diaphragm or a spermicide for contraception.

They should stay well hydrated.

These patients also should be maintained on some form of prophylactic antibiotic therapy. One alternative is to immediately take an antibiotic (nitrofurantoin, 100 mg twice daily for 3 days) at the first sign of recurrent symptoms. Another alternative is to take a dose of a drug such as nitrofurantoin (100 mg) or trimethoprim-sulfamethoxazole double-strength immediately after each episode of coitus. A third option is to take a single dose of one of these antibiotics every day. The choice between these methods should be based on the frequency of the patient's recurrences, with daily suppressive therapy reserved for the patients who are refractory to the other methods of prophylaxis.

6. What is the evidence for specific management and treatment recommendations

(Although this article is relatively old, it is of great importance because it showed clearly that the traditional definition of a positive urine culture, (greater than 100,000 colonies/ml) was not appropriate for acutely symptomatic patients. The authors demonstrated that this criterion identified only 51% of women whose bladders contained uropathogens. They also confirmed that in symptomatic patients, especially when the urine is obtained by catheterization, a colony count of greater than or equal to 100 colonies/ml was a much more sensitive predictor of bladder infection.)

(Although this article deals specifically with obstetric patients who have pyelonephritis, it illustrates the point that approximately 25% of strains of E. coli have become resistant to ampicillin, an observation that argues against use of this antibiotic as empiric treatment for UTIs in pregnant women.)

(This article was written by two recognized experts in the field of infectious disease and provides an excellent review of the pathophysiology, microbiology, diagnosis and management of both lower and upper urinary tract infections.)

(The authors showed that over time, uropathogens causing acute cystitis in women became increasingly resistant to ampicillin, cephalothin and trimethoprim-sulfamethoxazole. However, susceptibility to nitrofurantoin and ciprofloxacin remained high.)

(This paper is an excellent review of the diagnosis and management of acute cystitis and mild pyelonephritis in non-pregnant women. The author provides particularly useful information about rapid diagnosis with urine dipstick assessment and confirms the value of 3-day therapy in appropriately selected patients. He also addresses different strategies for preventing recurrent infections.)

(This article provides additional information about the suboptimal effect of ampicillin/amoxicillin-containing agents in the treatment of uncomplicated cystitis in women. The authors suggest that even the combination drug, amoxicillin-clavulanate, may not be fully effective in eradicating vaginal colonization with E. coli, thus leaving the patient susceptible to reinfection by these organisms.)

(The authors used a novel “dipslide” methodology to assess for asymptomatic bacteriuria in pregnancy. They noted that the simpler dipstick test for nitrites and leukocyte esterase had relatively low sensitivity (54%) in screening for asymptomatic bacteriuria. In contrast, patients with a positive dipslide had a 98% probability of having a positive culture. Conversely, if the dipslide was negative, the probability of a positive culture was < 1%.)

(The authors conducted a randomized trial of continuous catheterization versus intermittent catheterization in laboring women who received epidural analgesia. The rate of bacteriuria was higher in women who had intermittent catheterization.)

(This article presents an informative comparison of culture results [catheterized specimens versus midstream clean catch specimens] in premenopausal women with acute cystitis. Midstream specimens were more likely to be positive [78% vs 70%]. The presence of E. coli in the midstream culture was highly predictive of a positive culture by catheterization, even using a cut-off of only 100 colonies/ml [positive predictive value - 93%]. However, the presence of enterococci and group B streptococci, at any colony count, was not predictive of a positive culture obtained by catheterization.)

(The authors compared three different methods of urine collection to identify asymptomatic bacteriuria in pregnant women: first morning void, midstream specimen (void without further instructions), and midstream clean-catch void. Contamination rates were similar in the three groups, and the extra preparation associated with obtaining the first morning void or a clean-catch midstream specimen produced no measurable benefit.)

(In a prospective, randomized, double-blinded, controlled trial, the authors evaluated the effectiveness of cranberry juice capsules in preventing UTI after elective gynecologic surgery, during which a urinary catheter was placed. The use of cranberry extract capsules reduced the rate of UTI by half, compared to placebo.)

(The authors conducted a randomized, double-blind, placebo-controlled trial in women having reconstructive pelvic surgery. Patients were randomized to nitrofurantoin, 100 mg daily during catheterization, or placebo. The key outcome measure was the rate of UTI within 3 weeks of surgery. The rate of infection was 22% in patients who received nitrofurantoin and 13% in women who received placebo (p=.12). The authors concluded that, in this select group of patients, prophylaxis was not effective in reducing the frequency of postoperative infection.)